Abstract 2283: <i>SLC25A46</i> shows potential as a novel genetic regulator in breast cancer development
Authors: Heather K. Beasley, Ky'Era V. Actkins, Tyne Miller-Flemming, Bret C. Mobley, Lea Davis, Antentor O. Hinton, Nancy J. Cox
Journal: Cancer Research (2022)

Abstract SLC25A46 is a part of the mitochondrial solute carrier family (SLC25) and acts as a transporter transferring lipids between the mitochondria and endoplasmic reticulum space. SLC25A46 is expressed in the mitochondrial outer membrane, where it plays a significant role in regulating mitochondrial dynamics, cristae maintenance, and mitochondrial respiratory function. SLC25A46 prevents the formation of hyperfilamentous mitochondria and interacts with novel mitochondrial fusion proteins such as MFN-2 and OPA1 and the cristae organizing complex, MICOS. Notably, research has shown that a first-in-class, small molecule-specific OPA1 inhibitor can be used pharmacologically to curtail tumor growth; however, the OPA1 inhibitor did not explore how the interacting partner, SLC25A46, was affected by such inhibition. Indeed, novel targets are needed for advanced breast cancers as a means of therapeutic interventions. Considering the critical role of SLC25A46, we sought to investigate novel mitochondrial proteins that are understudied in breast cancer. We applied a statistical framework to calculate predicted gene expression for SLC25A46 in 70,349 patients of European descent in BioVU, the Vanderbilt University Medical Center (VUMC) biorepository linked to de-identified electronic health records (EHRs). A genetically predicted gene expression model for SLC25A46 was trained on directly measured RNA-seq data across 17 tissues from the Genotype-Tissue Expression (GTEx) Project. We then fitted a multivariable logistic regression model to test SLC25A46 predicted expression against 1,704 phenotypes for each tissue. We observed that patients with high predicted expression of SLC25A46 were more likely to receive diagnosis of ‘abnormal findings in mammograms’ (P=2.76E-06, OR=2.26) in adipose subcutaneous tissues. Likewise, we found yet another significant association with ‘lump or mass in breast’ (P=8.9E-06, OR=2.61) in adipose subcutaneous tissues. These results pass their individual Bonferroni correction that was applied separately for each tissue, but fell short of passing a strict multiple testing threshold that accounted for all tissues. Given the association between SLC25A46 and abnormal phenotypes that are commonly coded for patients in relation to breast cancer, we conducted a linear regression model with SLC25A46 and ionized calcium and found a modest association (P=0.03, OR=1.02). Elevated serum levels of calcium are frequently observed in advanced breast cancer. Additionally, proteins that interact with SLC25A46 such as OPA1, are overexpressed in breast cancer. We further constructed a polygene score to determine the effects of these genes in all breast cancer phenotypes. Together, these data suggest that SLC25A46 has implications in breast cancer as a novel target in cancer development. Citation Format: Heather K. Beasley, Ky'Era V. Actkins, Tyne Miller-Flemming, Bret C. Mobley, Lea Davis, Antentor O. Hinton, Nancy J. Cox. SLC25A46 shows potential as a novel genetic regulator in breast cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2283.